Brihad Abhyankar

The safety of vedolizumab for ulcerative colitis and Crohn's disease

Objective Vedolizumab is a gut-selective antibody to α4β7 integrin for the treatment of ulcerative colitis (UC) and Crohns disease (CD). We report an integrated summary of the safety of vedolizumab. Design Safety data (May 2009–June 2013) from six trials of vedolizumab were integrated. Adverse events were evaluated in patients who received ≥1 dose of vedolizumab or placebo and were reported as exposure-adjusted incidence rates as the number of patients experiencing the event per 100 person-years (PYs) of exposure. Predictors of serious infection were assessed using a Cox proportional hazards model. Results In total, 2830 patients had 4811 PYs of vedolizumab exposure (median exposure range, 1–1977 days). No increased risk of any infection or serious infection was associated with vedolizumab exposure. Serious clostridial infections, sepsis and tuberculosis were reported infrequently (≤0.6% of patients). No cases of progressive multifocal leucoencephalopathy were observed. Independent risk factors for serious infection in UC were prior failure of a tumour necrosis factor α antagonist (HR, 1.99; 95% CIs 1.16 to 3.42; p=0.0122) and narcotic analgesic use (HR, 2.68; 95% CI 1.57 to 4.58; p=0.0003), and in CD were younger age (HR, 0.97; 95% CI 0.95 to 0.98; p<0.0001), corticosteroid (HR, 1.88; 95% CI 1.35 to 2.63; p=0.0002) or narcotic analgesic use (HR, 2.72; 95% CI 1.90 to 3.89; p<0.0001). Investigator-defined infusion-related reactions were reported for ≤5% of patients in each study. Eighteen vedolizumab-exposed patients (<1%) were diagnosed with a malignancy. Conclusions Vedolizumab has a favourable safety profile with low incidence rates of serious infections, infusion-related reactions and malignancies over an extended treatment period. Trial registration number NCT01177228, NCT00619489, NCT00783718, NCT00783692, NCT01224171, NCT00790933.

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.

Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease

Vedolizumab is a gut‐selective immunoglobulin G1 monoclonal antibody to α4β7 integrin for the treatment of Crohns disease (CD) and ulcerative colitis (UC). Prospective clinical studies of vedolizumab in pregnancy have not been conducted; therefore, existing safety data of vedolizumab in pregnancy were examined.

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.

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy.

Background: Vedolizumab is a gut-selective &agr;4&bgr;7 integrin antagonist for the treatment of moderately to severely active Crohns disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-&agr;) antagonist therapy (TNF-naïve) or who had discontinued TNF-&agr; antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). Methods: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ⩽150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. Results: Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-&agr; antagonist failure or the number of prior TNF-&agr; antagonists failed. Safety profiles were similar in both subpopulations. Conclusions: Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-&agr; antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.

Sa1123 Infusion-Related Reactions With Vedolizumab Treatment in Patients With UC or CD During the GEMINI 1 and GEMINI 2 Clinical Trials

Introduction: Infections are an important concern in patients with inflammatory bowel diseases (IBD; Crohns disease (CD), ulcerative colitis (UC)) treated with immunosuppressive therapy. This is particularly so in those with significant co-morbidity, a population commonly excluded from clinical trials. Diabetes affects 9.3% of Americans and in increasing in prevalence. Infections commonly complicate diabetes which has itself been hypothesized to have an immunosuppressive effect. However, whether it confers additional risk of infections over immunomodulator therapy has not been examined previously. Methods: Using a validated, multi-institutional IBD cohort, we identified all patients who received at least one prescription for immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate). We identified diabetes and infections according to the corresponding ICD-9 codes. Our primary outcome was infection within 1 year of the first prescription of the immunomodulator. Multivariate logistic regression was used to estimate the independent association between diabetes and infection adjusting for relevant confounders including age, gender, comorbidity, and confounding medications. Results: Our study included 2,766 patients receiving at least one prescription for immunomodulators among whom 210(8%) developed an infectious complication within 1 year of the first prescription. Patients who developed an infection were likely to be older (46 years vs. 41 years, p < 0.001), female (58% vs. 52%), and have one or more additional comorbidity (95% vs. 70%). They were also more likely to have received a prescription for steroids (62 vs. 31%) but similar in initiation of anti-TNF therapy within that year (22% vs. 19%). Only 8% of those without an infection had diabetes compared to 19% of those who developed an infection within 1 year (p < 0.001) ( Figure). The most common infections in both groups were sepsis, pneumonia, cellulitis, and urinary tract infection. In multivariate analysis, diabetes was independently associated with a nearly twofold increase in risk of infections (OR 1.76, 95% CI 1.17 2.64) despite adjusting for age, other comorbidity, and medications. Conclusions: Diabetes is an independent risk factor for infection in IBD patients using immunomodulator therapy. Counseling and monitoring for such risks in addition to ensuring appropriate prophylaxis against preventable infections may help improve patient outcomes.

DOP073 Efficacy of induction treatment with vedolizumab for patients with Crohn's disease who have experienced tumour necrosis factor antagonist failure or are tumour necrosis factor antagonist naive

W.J. Sandborn1, P. Rutgeerts2 *, J. Xu3, B. Abhyankar4, I. Fox5. 1University of California San Diego, Division of Gastroenterology, La Jolla, United States, 2Katholieke Universiteit and University Hospital Gasthuisberg, Division of Gastroenterology, Leuven, Belgium, 3Takeda Pharmaceuticals International Company, Biostatistics, Cambridge, United States, 4Takeda Development Centre (Europe) Ltd, Clinical Science, London, United Kingdom, 5Takeda Pharmaceuticals International Company, Clinical Development, Cambridge, United States

Editorial: vedolizumab in pregnancy - is gut selectivity as good for baby as it is for mum? Authors’ reply

transmission of antibodies from mother to fetus. J Reprod Immunol 1997; 37: 1–23. 7. Chakraborti TK. Pharmacology review(s) of vedolizumab (Entyvio, MLN0002), 2013. Food and Drug Administration Center For Drug Evaluation and Research. Available at: http:// www.accessdata.fda.gov/drugsatfda_docs/nda/2014/ 125476Orig1s000PharmR.pdf (Accessed 27 February 2017). 8. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2013; 11: 286–92. 9. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology 2016; 151: 110–9. 10. Mahadevan U, Martin C, Kane SV, et al. Do infant serum levels of biologic agents at birth correlate with risk of adverse outcomes? results from the PIANO registry. Gastroenterology 2016; 150: S91–2. A437.

Letter: vedolizumab drug levels in cord and maternal blood in women with inflammatory bowel disease-authors’ reply

Guarantor of the article: MJ. Author contributions: MJ was responsible for the study concept and design; acquisition of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; obtaining funding; and study supervision. JK and DCB were responsible for acquisition of data; and critical revision of the manuscript for important intellectual content. BB was responsible for the performance of the vedolizumab analysis; and critical revision of the manuscript for important intellectual content. All authors approved the final version of the manuscript.