Efficacy and Safety of Subcutaneous Vedolizumab in Patients With Moderately to Severely Active Crohn’s Disease: Results From the VISIBLE 2 Randomised Trial

Abstract Background and Aims To report results from VISIBLE 2, a randomised, double-blind, placebo-controlled, phase 3 trial evaluating a new subcutaneous [SC] vedolizumab formulation as maintenance treatment in adults with moderately to severely active Crohn’s disease [CD]. Methods Following open-label vedolizumab 300 mg intravenous induction therapy at Weeks 0 and 2, Week 6 clinical responders (≥70-point decrease in CD Activity Index [CDAI] score from baseline) were randomised 2:1 to receive double-blind maintenance vedolizumab 108 mg SC or placebo every 2 weeks until Week 50. Assessments at Week 52 included clinical remission [primary endpoint; CDAI ≤150], enhanced clinical response [≥100-point decrease in CDAI from baseline], corticosteroid-free clinical remission among patients using a corticosteroid at baseline, clinical remission in anti-tumour necrosis factor [anti-TNF]-naïve patients, and safety. Results Following vedolizumab intravenous induction, 275 patients were randomised to vedolizumab SC and 135 to placebo maintenance. At Week 52, 48.0% of patients receiving vedolizumab SC versus 34.3% receiving placebo were in clinical remission [p = 0.008]. Enhanced clinical response at Week 52 was achieved by 52.0% versus 44.8% of patients receiving vedolizumab SC versus placebo, respectively [p = 0.167]. At Week 52, 45.3% and 18.2% of patients receiving vedolizumab SC and placebo, respectively, were in corticosteroid-free clinical remission, and 48.6% of anti-TNF-naïve patients receiving vedolizumab SC and 42.9% receiving placebo were in clinical remission. Injection site reaction was the only new safety finding observed for vedolizumab SC [2.9%]. Conclusions Vedolizumab SC is an effective and safe maintenance therapy in patients with CD who responded to two infusions of vedolizumab intravenous induction therapy.


Introduction
Crohn's disease [CD] is an inflammatory bowel disorder characterised by abdominal pain, diarrhoea, fatigue, and weight loss. 1,2 When inadequately controlled, it can lead to structural bowel damage with stricture and/or penetrating disease and loss of function, negatively affecting quality of life [QoL] and work productivity. 3 Vedolizumab, an anti-α 4 β 7 integrin that selectively blocks lymphocyte trafficking to the gut, is approved worldwide as an intravenous [IV] formulation to treat moderately to severely active ulcerative colitis [UC] and CD. [4][5][6][7] The efficacy and safety of vedolizumab IV 300 mg as both induction and maintenance therapy is well established. [8][9][10] Most advanced treatments for moderately to severely active UC and CD are administered as IV infusions or subcutaneous [SC] injections. 11,12 Patients may view an SC formulation as less time consuming and more convenient, 13,14 especially for maintenance therapy. An SC formulation of vedolizumab [vedolizumab SC] was developed to provide an alternative route of vedolizumab administration and was approved in 2020 for use in UC and CD in Europe, Canada, and Australia as maintenance therapy (108 mg every 2 weeks [Q2W]). 7,15, 16 Vedolizumab SC was clinically evaluated in patients with moderately to severely active UC and CD. Results from the phase 3 VISIBLE 1 trial in UC have been reported. 17 Significantly higher rates of clinical remission [defined as a total Mayo score ≤2 and no subscore >1] and endoscopic improvement were observed with vedolizumab SC maintenance therapy compared with placebo at Week 52 in patients with UC who had responded to vedolizumab IV induction. 17 Moreover, the efficacy and safety profiles of vedolizumab SC maintenance were comparable to those of the vedolizumab IV reference arm. 17 Here, we report efficacy and safety results from the phase 3 VISIBLE 2 trial evaluating vedolizumab SC maintenance treatment in patients with CD.

Methods
As part of the VISIBLE 2 study, all patients provided written informed consent, and the trial was approved by the institutional review board of each participating institution.

Study population
Adults aged 18-80 years with moderately to severely active CD diagnosed ≥3 months before study enrolment, who had previously demonstrated an inadequate response to or intolerance of corticosteroids [CS], immunomodulators, and/or anti-tumour necrosis factor [ 18 Clinical remission cut-offs for PRO2 and PRO3 were chosen to correspond with CDAI <150, and the third definition corresponded with two of the three optimal cut points for CDAI remission. 18 Exploratory efficacy endpoints also included changes in inflammation biomarkers of CD activity, including faecal calprotectin and C-reactive protein [CRP] assessed using stool and blood samples, respectively, collected at screening and Weeks 0 [CRP only], 6, 30, and 52. Some patients who enrolled at select sites volunteered to undergo ileocolonoscopies at screening and at the Week 52/early termination visit; endoscopic response and endoscopic remission were assessed based on the Simple Endoscopic Score for CD.
Lack of efficacy was defined as disease worsening [≥100 point increase in CDAI score from the Week 6 value on two consecutive visits and a minimum CDAI score of 220 points], need for rescue medication, or need for surgery. Any new medication or escalation of dose above baseline dose [except for anti-diarrhoeals] was considered a rescue medication. In regard to CS, an increase back to baseline dose in patients undergoing tapering was not considered rescue medication. Patients who discontinued the study due to lack of efficacy and showed disease worsening on or after Week 6, or those who received rescue medication beyond Week 14, were eligible to enter an open-label extension [OLE; NCT02620046] study to receive vedolizumab SC after completion of the Week 52/early termination trial assessments. 19 These patients were also eligible for dose escalation in the OLE study from Q2W to weekly dosing of vedolizumab SC. Patients who withdrew from the study and did not participate in OLE were managed outside the study.

Health-related QoL and work productivity
Patients completed validated instruments to measure QoL and work productivity at Weeks 0, 6, 30, and 52, including the Inflammatory Bowel Disease Questionnaire, 20 the EuroQol 5-Dimensions visual analogue scale, and the Work Productivity and Activity Impairment-CD scale; see Supplementary Methods for more information.

Safety/tolerability
Safety assessments included all adverse events [AEs], AEs of special interest, serious AEs, vital signs, results of standard laboratory clinical chemistry, haematology, coagulation and urinalysis tests, and 12-lead electrocardiogram results. All AEs, regardless of causality, were reported and monitored from study enrolment. All AEs were coded using the Medical Dictionary for Regulatory Activities. Pre-defined AEs of special interest included serious infections, progressive multifocal leukoencephalopathy [PML], liver injury, malignancies, infusion-related or injection site reactions, and systemic reactions/hypersensitivities.

Pharmacokinetics and immunogenicity
Blood samples were drawn for determination of vedolizumab serum concentrations pre-dose at Weeks 0, 6,8,14,22,30,38,46, 50, and 68; at any time during the study visits at Weeks 7, 51, and 52; at any unscheduled visit due to disease exacerbation; and at the final safety follow-up visit. Vedolizumab serum concentrations were determined using a validated sandwich enzyme-linked immunosorbent assay, with a limit of quantification of 0.2 μg/ml. 21 Vedolizumab anti-drug antibody [ADA] titres were assessed from blood samples collected at Weeks 0, 6,8,14,22,30,38,46, and 52, and at Week 68/final safety visit. Assessments of ADAs and neutralising ADAs were determined using validated drug-tolerant [≥50 µg/ml at 500 ng/ml positive control] electrochemiluminescence assays. 22

Overview
Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of placebo or vedolizumab as maintenance therapy. Statistical analyses were performed using version 9.4 of the SAS software [Cary, NC, USA]. Other than the biomarker endpoints, where analysis was based on observed data, missing data for continuous endpoints were imputed using the last available post-baseline observation carried forward method. Missing data for proportion-based endpoints used non-responder imputation, in which any patient with missing information for determination of endpoint status was considered as a treatment failure/non-responder in the analysis. All confidence intervals [CIs], statistical tests, and resulting p-values were reported as two-sided and assessed at α = 0.05 significance level. As a sensitivity analysis, primary and secondary endpoints were also analysed in the per-protocol set, which included all patients who did not violate the terms of the protocol in a way that would significantly impact on the study. All safety analyses were performed by treatment arm in the safety analysis set, which included all patients who received at least one dose of maintenance SC drug; incidence rates were summarised by treatment arm and no statistical comparisons were made.

Sample size calculation
Assuming a clinical remission rate of 38% for vedolizumab and 22% for placebo at Week 52 after maintenance treatment, a sample size of 258 patients in the vedolizumab arm and 129 patients in the placebo arm was determined to provide 90% power to detect a treatment effect at a two-sided 0.05 level of significance. To ensure a randomised sample size of 387 patients, assuming 47% of patients entering induction would achieve clinical response at Week 6, approximately 824 patients needed to enrol in the study.

Primary and secondary efficacy analyses
Count, percentage, and associated 95% CI using the Clopper-Pearson method were reported for each treatment arm. The p-value and point estimates of the treatment difference for efficacy endpoints were analysed using the Cochran-Mantel-Haenszel test, adjusted for randomisation stratification factors (concomitant use of oral CS [except for the analysis of CS-free remission], clinical remission status at Week 6, and previous anti-TNF therapy failure/exposure or concomitant immunomodulator use). To control the overall type I error rate for the comparison between vedolizumab SC and placebo arms for the primary and secondary endpoints, a fixed-sequence statistical testing approach was applied. Statistical testing of each endpoint proceeded according to the endpoint rank order only until an endpoint was not statistically significant [p <0.05]. The remaining endpoints were not formally tested and p-values were considered nominal. Exploratory analyses were performed on the primary and all secondary endpoints to evaluate the treatment effect across subpopulations, with point estimates of the absolute treatment difference based on crude estimates and associated 95% CIs reported for subpopulations with ≥10 patients in both treatment arms.

Study oversight
This study was overseen by the sponsor, Takeda, and conducted by contracted clinical investigators. Medical and clinical monitoring was conducted by the sponsor and its designated representatives. A data safety monitoring board, independent of the sponsor, regularly reviewed unblinded safety data. An independent adjudication committee was established to review and adjudicate potential PML events. The clinical study protocol and all applicable protocol amendments, the investigator's brochure, a sample informed consent form, and other study-related documents were reviewed and approved by the local or central institutional review boards of all study sites. This study was conducted in compliance with the informed consent regulations stated in the Declaration of Helsinki, International Conference on Harmonisation Guidelines for Good Clinical Practice, and all applicable local laws and regulations.

Patient and public involvement
Patients were not involved in the design, recruitment, conducting, or dissemination of the results of the study.

Data availability
The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants' data supporting the results reported in this article, will be made available within 3 months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after de-identification, in compliance with applicable privacy laws, data protection, and requirements for consent and anonymisation. Data are available upon request via application at [https://search. vivli.org]. Baseline patient demographics were generally balanced between the two treatment arms [ Table 1]. There were some differences in disease characteristics. More patients receiving vedolizumab SC versus placebo had ileum-only disease presentation [ Figure 1]. The results of the primary and secondary endpoints analysed in the per-protocol set and in a post hoc sensitivity analysis excluding the 18 patients who did not meet clinical response criteria, and who were randomised to maintenance therapy, were generally consistent with the results in the full analysis set [Supplementary Treatment differences with clinical remission at Week 52 across a range of subgroups based on patient and disease characteristics were generally consistent with the overall population [ Figure 2]. Notably, a treatment difference in clinical remission favouring vedolizumab SC over placebo was observed in patients with colonic or ileocolonic disease localisation, but not with ileum-only disease. Treatment differences with enhanced clinical response were generally consistent with the overall population, including in all anti-TNF subgroups [Supplementary  Patients receiving vedolizumab SC following vedolizumab IV induction showed greater improvements in CDAI scores over time compared with patients receiving placebo for maintenance [ Figure  3]. Following vedolizumab IV induction, a higher proportion of patients on maintenance treatment with vedolizumab SC than placebo reported improvements in PRO2 and PRO3 [ Figure 4]. The limited ileocolonoscopy data available from a subset of patients are presented in the Supplementary Results, available as Supplementary data at ECCO-JCC online.

Biomarker endpoints
There were improvements in faecal calprotectin and serum CRP concentrations over time [ Figure 5]. Normal [≤250 µg/g] faecal calprotectin concentrations at Week 52 were detected in 60.5% versus 31.7% of patients in the vedolizumab SC versus placebo arms, respectively [Supplementary Figure 4 and

Health-related QoL and work productivity
Early improvements in health-related QoL achieved during vedolizumab induction were maintained to a greater extent in patients receiving vedolizumab SC maintenance compared with placebo [ Supplementary Figures 5-7

Safety/tolerability
Overall safety results were similar between the vedolizumab SC and placebo maintenance arms, with most AEs considered mild to moderate [         8 Treatment effects across the secondary efficacy endpoints consistently favoured vedolizumab SC over placebo in VISIBLE 2. The firstranked secondary endpoint of enhanced clinical response, although not statistically significant, was higher with vedolizumab SC than placebo [treatment effect 7.3%]. In the next secondary endpoint, the proportion of patients achieving CS-free clinical remission at 52 weeks demonstrated a clinically meaningful treatment effect [27.1%] of vedolizumab SC over placebo; this comparison was not assessed for significance due to the pre-specified rank order analysis of secondary endpoints. The results for the final secondary endpoint The safety analysis set included all patients who were randomised to the maintenance phase and received at least one dose of study drug. Week 0 Baseline

Pharmacokinetics and immunogenicity
Week 6 Week 30 Week of clinical remission in the anti-TNF-naïve population were similar between vedolizumab SC and placebo, with a small treatment difference [4.3%] for vedolizumab SC over placebo.
Higher rates of CDAI-based PRO2 and PRO3 clinical remission were observed with vedolizumab SC maintenance treatment compared with placebo, suggesting that vedolizumab SC may enhance relief of patient-perceived symptoms.
The limited treatment effects observed for vedolizumab SC versus placebo for some of the key endpoints, such as enhanced clinical response and clinical remission rates in anti-TNF-naïve patients in VISIBLE 2, are not fully understood, but higher placebo rates compared with GEMINI 2 may have an impact. Several factors might have, at least in part, contributed to the higher placebo rates observed in VISIBLE 2. First, differences in the VISIBLE 2 and GEMINI 2 study designs may have led to expectation bias: all patients in the VISIBLE 2 study received open-label vedolizumab IV induction, whereas GEMINI 2 used a double-blind, placebo-controlled, induction treatment phase. At Week 6 in the VISIBLE 2 study, clinical remission was observed in 50.6% of patients who were randomised to maintenance phase. Clinical efficacy following induction appears higher than that observed in the GEMINI 2 study. 8 There were no noticeable differences in the baseline demographics and disease characteristics between patients with clinical response at Week 6 who were assigned to the placebo arm in the maintenance phase in the VISIBLE 2 and GEMINI 2 studies. 8  . It is well known that biologic therapies are more effective in patients with colon involvement than in those with ileum-only disease localisation. 25 The relevance of this imbalance relates to evidence that patients with isolated ileal CD, as opposed to colonic CD, are significantly less likely to achieve a response or remission with the biologic intervention. 4 Subgroup analyses according to TNF status showed treatment differences in favour of vedolizumab SC over placebo for key endpoint analyses at Week 52 in both anti-TNF-naïve and -failure subgroups, with differences in clinical remission more pronounced in patients with history of previous anti-TNF failure. Treatment differences in CS-free clinical remission were similar in anti-TNF-naïve and -failure patients.
The safety of vedolizumab SC is consistent with the known safety profile of vedolizumab IV therapy in patients with CD, with the exception of injection site reactions, which occurred in 2.9% [eight of 275] of patients in VISIBLE 2. 8,26 The observed pharmacokinetic vedolizumab exposure after maintenance on the SC formulation in CD patients reported in VISIBLE 2 was comparable with the same treatment regimen in UC patients in VISIBLE 1. 17 Immunogenicity rates in VISIBLE 2 were similar to previous reports. 8,10,27,28 This study had several limitations. A vedolizumab IV reference arm was not included. Whereas comparable vedolizumab exposure and clinical efficacy with vedolizumab 300 mg IV Q8W and vedolizumab 108 mg SC Q2W maintenance is well established in UC patients, 17 these results would have provided additional data specific to CD patients. Another limitation is that the results of endoscopic assessments were not essential for inclusion criteria, mirroring the design of the GEMINI 2 study, and endoscopic outcomes were assessed on voluntary basis. Based on comparable efficacy of vedolizumab SC to vedolizumab IV in the GEMINI 2 study, combined with the results of the VERSIFY trial evaluating vedolizumab IV, which showed that clinical remission/response was achieved as well as endoscopic improvements in patients with CD, it is reasonable to speculate of comparable clinical benefits with vedolizumab SC. 8,29 These data represent efficacy and safety after 1 year of treatment. Additional data are being collected from this patient cohort during the ongoing VISIBLE open-label extension study [NCT02620046], to evaluate the long-term benefits of vedolizumab SC maintenance treatment. 19 In conclusion, VISIBLE 2 trial results establish the efficacy and safety of vedolizumab SC as maintenance treatment for patients with moderately to severely active CD who responded to vedolizumab IV induction. Vedolizumab SC maintenance treatment of CD demonstrated clinically meaningful and statistically significant superiority over placebo for the primary endpoint of clinical remission at Week 52. In addition, the clinically meaningful treatment difference observed for the CS-free clinical remission endpoint supports the CS-sparing effect of vedolizumab SC as maintenance treatment in CD. Vedolizumab SC was well tolerated with no new safety signals All patients with missing data for determination of endpoint status were categorised as non-remitters. Overall ADA was defined from baseline [inclusive] through Week 52.
ADA, anti-drug antibody; SC, subcutaneous. a The safety analysis set included all patients who were randomised to the maintenance phase and received at least one dose of study drug. b Patients in the placebo arm received open-label vedolizumab during the 6-week induction phase but received placebo during the maintenance phase. observed, with the exception of injection site reactions. These results support vedolizumab SC as an important treatment option for patients who require maintenance therapy for CD. Vedolizumab is the first gut-targeted biological treatment for inflammatory bowel disease to offer the option of both IV and SC routes of administration for maintenance therapy.