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.

Incidence of Arthritis/Arthralgia in Inflammatory Bowel Disease with Long-term Vedolizumab Treatment: Post Hoc Analyses of the GEMINI Trials.

BACKGROUND AND AIMS: Extraintestinal manifestations [EIMs] such as arthritis/arthralgia are common in inflammatory bowel disease. We performed post hoc analyses of data from the GEMINI studies to evaluate the effect of vedolizumab, a gut-selective anti-trafficking agent, on arthritis/arthralgia. METHODS: Sustained resolution of baseline arthritis/arthralgia, worsening of baseline arthritis/arthralgia, the occurrence of new arthritis/arthralgia, and the composite of new/worsening arthritis/arthralgia were evaluated. Cox modelling was used for time-to-event analysis. The influence of corticosteroid-tapering was also investigated. RESULTS: In Crohn's disease [CD] patients, vedolizumab was significantly less likely than placebo to be associated with new/worsening arthritis/arthralgia (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.44-0.89). Similar incidences of sustained resolution of arthritis/arthralgia occurred with vedolizumab and placebo. In CD patients on corticosteroids at baseline, a decrease in corticosteroid dose increased the risk of new/worsening arthritis/arthralgia (odds ratio [OR], 7.49; 95% CI, 3.50-15.97) regardless of treatment; and in those achieving corticosteroid-free status, arthritis/arthralgia was less likely with vedolizumab than with placebo [HR, 0.14; 95% CI, 0.05-0.35]. In ulcerative colitis [UC] patients, vedolizumab and placebo showed a similar incidence of new/worsening of arthritis/arthralgia. In UC patients on corticosteroid at baseline, arthritis/arthralgia was more likely in those achieving corticosteroid-free status than in those continuing corticosteroids (HR 2.63 [95% CI 1.13-6.11]); and in those achieving corticosteroid-free status, the incidence of arthritis/arthralgia was similar with vedolizumab and placebo. CONCLUSIONS: Vedolizumab therapy was associated with a reduced likelihood of new/worsening arthritis/arthralgia in CD and no increased incidence of these events in UC. STUDIES INCLUDED [CLINCIALTRIALS.GOV, NUMBER]: GEMINI 1 [NCT00783718]; GEMINI 2 [NCT00783692]; GEMINI 3 [NCT01224171].

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.

What Is the Risk of Progressive Multifocal Leukoencephalopathy in Patients With Ulcerative Colitis or Crohn's Disease Treated With Vedolizumab?

Background: Progressive multifocal leukoencephalopathy is a serious condition linked to certain diseases and immunosuppressant therapies, including the α4 integrin antagonist natalizumab. No cases have been reported to date with vedolizumab, a selective antagonist of the α4ß7 integrin expressed on gut-homing lymphocytes. This analysis aimed to describe the current and future expected occurrence of progressive multifocal leukoencephalopathy with vedolizumab use, were the risk the same as in other populations in which this disease has been studied. Methods: The expected number of vedolizumab-associated progressive multifocal leukoencephalopathy cases was estimated up to May 19, 2016, and modeled up to 2034. These estimates were based on the cumulative exposure to the drug, assuming an equivalent risk to that of patients treated with natalizumab or those from other reference populations where progressive multifocal leukoencephalopathy has been examined. Future cases were modeled based on similar risks and projected sales. Results: The cumulative vedolizumab exposure was estimated at 54,619 patient-years, with a 95% confidence interval of 0.0 to 6.75 cases per 100,000 patient-years. An estimated 30.2 (95% confidence interval, 19.4-40.9) cases of progressive multifocal leukoencephalopathy would have occurred if vedolizumab had the same risk as that of natalizumab. There would be a 50% chance of the first case occurring by 2018, assuming an equivalent risk to the general population. Conclusions: These analyses indicate that the risk of progressive multifocal leukoencephalopathy with vedolizumab is small, and unlikely to be above 6.75 cases per 100,000 patient-years.

Bone marrow transplantation in AML, and socioeconomic class: a UK population-based cohort study.

BACKGROUND: We have previously shown that in the UK mortality in people with Acute Myeloid Leukaemia (AML) was nearly 50% greater among the most socio-economically deprived. The aim of this study was to determine whether AML patients from lower socioeconomic classes had a lower chance of receiving a bone marrow transplant. METHODS: Using Hospital Episode Statistics (HES) data, we identified all incident cases of AML admitted to UK hospitals between 1998 and 2007. We calculated the number of bone marrow transplantations undertaken in AML patients, stratifying our results by gender, age at diagnosis, year of diagnosis, degree of socioeconomic deprivation and co-morbidity. We used logistic regression to calculate odds ratios for bone marrow transplantation, adjusting for gender, age at diagnosis, year of diagnosis, degree of socioeconomic deprivation and co-morbidity score. RESULTS: We identified a total of 23 910 incident cases of AML over this 10-year time period, of whom 1 140 (4.8%) underwent BMT. Bone marrow transplantation declined with increasing socioeconomic deprivation (p for trend < 0.001) such that people in the most deprived socioeconomic quintile were 40% less likely to have a transplant than those in the most advantaged group (Odds Ratio 0.60, 95% confidence interval 0.49, 0.73), even after adjusting for gender, age at diagnosis, year of diagnosis and co-morbidity. CONCLUSION: This large cohort study demonstrates that AML patients from lower socioeconomic classes are less likely to undergo bone marrow transplantation than their better off counter-parts.

The incidence of and mortality from leukaemias in the UK: a general population-based study.

BACKGROUND: The acute and chronic leukaemias constitute about 2.5% of all newly diagnosed malignancies and kill over 4000 people/year in the UK, yet there is little accurate up-to-date data on how the incidence of and mortality from leukaemias vary with socio-economic status in the UK. We aimed to quantify the incidence of and mortality from leukaemias in the UK and their variation with gender, age, year of diagnosis as well as socio-economic status. METHODS: All incident cases of leukaemia were identified in 'The Health Improvement Network' (THIN) General Practice dataset. Crude incidence rates and incidence rate ratios (using Poisson Regression) stratified by age, gender, year of diagnosis and socio-economic status were calculated. Median survival and hazard ratios for risk of death (using Cox regression) were then calculated, and stratified in a similar manner. RESULTS: A total of 4162 cases of leukaemia were identified, 2314 (56%) of whom were male. The overall incidence of leukaemia was 11.25 per 100,000 person-years. The age and gender distributions of ALL, AML, CLL and CML were similar to UK cancer registry data. The incidence of leukaemias was independent of socio-economic class. Median survival from leukaemia was 6.58 years and mortality increased with increasing age at diagnosis. The prognosis in AML was dismal and worsened with increasing socio-economic deprivation. For other leukaemias mortality was independent of socio-economic status. CONCLUSION: This is the first general population study to describe the incidence of and mortality from leukaemias in the UK by socio-economic status. Similar mortality across socio-economic gradients in the leukaemias studied suggests equal access to and uptake of services. The exception to this was in AML, where poorer survival in AML patients from lower socio-economic classes may represent a class bias in treatment offered and/or greater co-morbidity in these patients, and warrants further exploration.