Integrating efficacy and safety of vedolizumab compared with other advanced therapies to assess net clinical benefit of ulcerative colitis treatments: a network meta-analysis.

Objectives: Because only one head-to-head randomized trial of biologics for moderate-to-severe UC has been performed, indirect treatment comparisons remain important. This systematic review and network meta-analysis examined efficacy and safety of biologics and tofacitinib for moderate-to-severe UC, using vedolizumab as reference.Methods: Relevant studies (N = 19) of vedolizumab, adalimumab, infliximab, golimumab, ustekinumab, and tofacitinib were identified. Study design differences were addressed by assessing efficacy outcomes conditional on response at maintenance initiation. Primary analysis used fixed-effect models to estimate odds ratios for efficacy and safety endpoints.Results: Compared with vedolizumab 300 mg, adalimumab 160/80 mg was associated with less clinical remission (odds ratio, 0.69 [95% credible interval, 0.54-0.88]), and infliximab 5 mg/kg was associated with more clinical remission (1.67 [1.16-2.42]) and response (1.63 [1.15-2.30]). Adalimumab 40 mg, golimumab 50 mg, and ustekinumab 90 mg Q12W had significantly lower clinical remission rates during maintenance (0.62 [0.45-0.86], 0.55 [0.32-0.95], and 0.59 [0.35-0.99]) versus vedolizumab 300 mg Q8W. Response results were similar. Tofacitinib 10 mg had the highest maintenance treatment efficacy estimates and highest infection risk.Conclusion: Network meta-analysis and novel integrated benefit-risk analysis suggest a potentially favorable efficacy-safety balance for vedolizumab vs adalimumab and other advanced UC therapies.

The Safety Profile of Vedolizumab in Ulcerative Colitis and Crohn's Disease: 4 Years of Global Post-marketing Data.

BACKGROUND AND AIMS: Vedolizumab is a gut-selective antibody to α 4  ß 7 integrin, approved to treat moderate-to-severe ulcerative colitis and Crohn's disease in adults. Clinical trial data on patients meeting protocol-specified criteria may not reflect real-world clinical practice. This is a descriptive analysis of 4 years of post-marketing safety data on vedolizumab. METHODS: The Vedolizumab Global Safety Database contains all adverse event reports collated by Takeda Pharmaceutical Company Ltd since vedolizumab approval [May 20, 2014]. Adverse event reports received between approval and May 19, 2018 were identified using Medical Dictionary for Regulatory Activities version 21.0 Preferred Terms. Adverse event frequencies were calculated and categorised. RESULTS: In approximately 208 050 patient-years of vedolizumab exposure, 32 752 patients reported 80 218 events. In patients with Crohn's disease or ulcerative colitis, 37 662 and 34 259 events occurred in 14 191 and 14 042 patients, respectively, and 8297 events occurred in 4519 individuals with other [off-label] or unreported indications. Overall, 5230 [14%; Crohn's disease] and 3580 [10%; ulcerative colitis] events were serious. Most frequently reported were gastrointestinal events (Crohn's disease, 6156 [16%]; ulcerative colitis, 5701 [17%]). Patients with Crohn's disease or ulcerative colitis reported 251 malignancies [<1%], 402 hepatobiliary events [<1%], and 5876 infections (1137 serious [19%], 301 opportunistic [5%]). Patients aged ≥70 years [2326 patients] reported <10% of events. CONCLUSIONS: Adverse event patterns were consistent with clinical trials, with no new safety concerns. Most reported events were non-serious and event frequency was low, considering patient-years of exposure. Although limitations of post-marketing safety reports require acknowledgement, these real-world data support a favourable safety profile of vedolizumab.

Vedolizumab use is not associated with increased malignancy incidence: GEMINI LTS study results and post-marketing data.

BACKGROUND: Vedolizumab is a gut-selective antibody to α4 ß7 integrin approved to treat moderate-to-severe Crohn's disease and ulcerative colitis in adults. Inflammatory bowel disease (IBD) and immunosuppressant use are associated with increased risk of malignancy. AIM: To analyse the incidence of malignancy with vedolizumab treatment in the GEMINI long-term safety (LTS) study and post-marketing (PM) setting. METHODS: Malignancy data from the LTS study (May 2009 to May 2018), and data from the vedolizumab Global Safety Database (20 May 2014 to 19 May 2018), were identified using Medical Dictionary for Regulatory Activities coding. The number of patients experiencing malignancies in the LTS study (excluding malignancies within 1 year following vedolizumab initiation) was indirectly standardised against the number expected, using age- and sex-specific rates in patients with IBD from Optum's Clinformatics™ Data Mart (CDM) database. RESULTS: Among 1785 patients with ≥1 year of follow-up post-vedolizumab initiation in the LTS study (total 5670 patient-years), observed numbers of malignancies were similar to those expected compared with CDM data (31 vs 29; ratio of observed to expected events = 1.08; P = 0.71; 95% confidence intervals [CI] 0.73, 1.53). The most common malignancies were renal and bladder (6). PM, 293 patients reported 299 malignancies (including malignancies within 1 year following vedolizumab initiation), in approximately 208 050 patient-years of vedolizumab exposure. Lower gastrointestinal malignancies were most common (59). CONCLUSIONS: The number of malignancies in the LTS study was similar to that expected from an IBD population with no statistically significant differences, although few confounders could be corrected for. Limitations of PM safety reporting require consideration; however, the number of malignancies with vedolizumab appeared low.

Vedolizumab use in patients with inflammatory bowel diseases undergoing surgery: clinical trials and post-marketing experience.

BACKGROUND: Patients with inflammatory bowel diseases frequently require surgery, but immunotherapies used in disease management may increase the risk of post-operative complications. We investigated frequencies of post-operative complications in patients who received vedolizumab-a gut-selective antibody approved for the treatment of moderately to severely active ulcerative colitis and Crohn's disease-in clinical-trial and post-marketing settings. METHODS: This post hoc analysis of safety data from GEMINI 1, GEMINI 2, and long-term safety studies included patients who had had colectomy or bowel surgery/resection. Data from the post-marketing Vedolizumab Global Safety Database were also analysed (data cutoff point: 19 May 2016). Adverse events relating to post-operative complications were identified using Medical Dictionary for Regulatory Activities preferred terms. RESULTS: Of 58 total surgeries in patients included in GEMINI 1 and GEMINI 2, post-operative complications were reported for 3/51 vedolizumab-treated patients (5.9%) and 1/7 placebo-treated patients (14.3%). In the long-term safety study, 157/2,243 patients (7%) had colectomy or bowel surgery/resection; of these 157 patients who underwent surgery, 11 (7%) experienced a post-operative complication. Median time between last pre-operative vedolizumab dose and surgery was 23 days in GEMINI 1, 20 days in GEMINI 2, and 39‒40 days in the long-term safety study. In the post-marketing setting, based on data covering approximately 46,978 patient-years of vedolizumab exposure, post-operative complications were reported in 19 patients. CONCLUSIONS: In clinical trials, complications of colectomy and bowel surgery/resection appeared infrequent, with minimal difference between vedolizumab and placebo. The frequency of post-operative complications in the post-marketing setting appears low.

Low Frequency of Opportunistic Infections in Patients Receiving Vedolizumab in Clinical Trials and Post-Marketing Setting.

Background: Vedolizumab (ENTYVIO) is a humanized α4ß7 integrin antagonist approved for the treatment of inflammatory bowel disease, which selectively blocks gut-specific lymphocyte trafficking. We evaluated the risk of opportunistic infections of interest in patients treated with vedolizumab. Methods: We determined the frequency of opportunistic infections and tuberculosis in patients receiving vedolizumab in phase 3 clinical trials and post-marketing settings. We also evaluated adverse events reported in the post-marketing setting in patients with a history of or concurrent hepatitis B/C virus infection. Results: The incidence of opportunistic infections in patients receiving vedolizumab was 0.7 (GEMINI 1 and 2 clinical trials) and 1.0 (long-term safety study) per 100 patient-years, with 217 events reported in approximately 114,071 patient-years of exposure (post-marketing setting). Most opportunistic infections were nonserious and the majority of patients continued treatment with vedolizumab. Clostridium difficile was the most commonly reported infection, with an incidence rate of 0.5 per 100 patient-years (clinical trials). Tuberculosis was reported at 0.1 per 100 patient-years (clinical trials), with 7 events in the post-marketing setting. No tuberculosis-related deaths were reported in either setting. No cases of progressive multifocal leukoencephalopathy were reported. In 29 patients with a history of or concurrent hepatitis B/C infection in the post-marketing setting, no viral reactivation was observed. Conclusions: Clinical trials and post-marketing data showed that the rate of serious opportunistic infections in patients receiving vedolizumab was low and most patients could continue vedolizumab treatment. The frequency of tuberculosis infection was also low and no hepatitis B/C viral reactivation was reported.

Respiratory Tract Infections in Patients With Inflammatory Bowel Disease: Safety Analyses From Vedolizumab Clinical Trials.

BACKGROUND AND AIMS: Vedolizumab, a humanised monoclonal antibody for the treatment of inflammatory bowel disease, selectively blocks gut lymphocyte trafficking. This may reduce the risk of respiratory tract infections [RTIs] compared with systemic immunosuppressive therapies. To assess this possibility, we evaluated the rates of RTIs in clinical trials of vedolizumab. METHODS: Patient-level data from Phase 3 randomised controlled trials [RCTs] of vedolizumab in ulcerative colitis [UC; GEMINI 1] and Crohn's disease [CD; GEMINI 2], and a long-term safety study [UC and CD] were pooled. Cox proportional hazards models were used to estimate the incidence of upper RTIs [URTIs] and lower RTIs [LRTIs] with adjustment for significant covariates. RESULTS: In the RCTs [n = 1731 patients], the incidence of URTIs was numerically higher in patients receiving vedolizumab compared with those receiving placebo, although this difference was not statistically significant (38.7 vs 33.0 patients per 100 patient-years; hazard ratio [HR] 1.12; 95% confidence interval [CI]: 0.83-1.51; p = 0.463). The rate of LRTIs, including pneumonia, was numerically lower in the vedolizumab versus the placebo group: this difference was not statistically significant (7.7 vs 8.5 per 100 patient-years [HR 0.85; 95% CI: 0.48-1.52; p = 0.585]). Both URTIs and LRTIs were more frequent in patients with CD compared with UC. Most RTIs in patients receiving vedolizumab were not serious and did not require treatment discontinuation. CONCLUSIONS: Vedolizumab therapy was not associated with an increased incidence of respiratory tract infection compared with placebo.