Emerging Safety Profile of Vedolizumab: A novel, selective Integrin Inhibitor for the treatment of IBD

Abstract

INTRODUCTION: Vedolizumab, a humanized version of Act-1 1 (previously known as MLN0002, MLN02, LDP-02), is a monoclonal antibody to alpha4beta7 integrin. Vedolizumab inhibits lymphocyte trafficking to gastrointestinal tissue by blockingalpha4beta7 adhesion to MAdCAM-1 (mucosal vascular addressin cell adhesion molecule). Humanized Act-1 has demonstrated therapeutic activity in both ulcerative colitis (UC) and Crohn's disease (CD) trials 2,3. Because of its unique specificity for alpha4beta7 4 vedolizumab is not expected to lead to systemic opportunistic infections (OIs) such as progressive multifocal leukoencephalopathy (PML), observed in patients treated with a non-specific antagonist to alpha 4. We report safety findings from phase 1 and 2 clinical trials of vedolizumab and its precursor (LDP-02). METHODS: An integrated safety analysis was performed on data from 9 clinical trials (8 placebo controlled) in 579 healthy subjects and patients with IBD. 415 subjects received vedolizumab or its precursor at single or multiple doses up to 10 mg/kg intravenously for up to 4 doses. RESULTS: Overall, 348 (84%) of subjectswhoreceived drug/treatment reported at least one adverse event (AE) compared to 143 (87%) placebo subjects. The most common AEs among treated subjects were headache, nausea, exacerbation of ulcerative colitis, abdominal pain, fatigue and nasopharyngitis. Rates of serious adverse events were similar among treatment groups: 12% (50 subjects) in the drug treated group vs. 14% (23 subjects) in the placebo group. 135 (33%) treated subjects experienced at least 1 infection vs. 37 (23%) placebo subjects. The upper respiratory tract was the most common site of infection. Herpes labialis was reported by 11 (2.3%) treated subjects vs. 1 (0.6%) in placebo, and mucosal candidiasis by 5 (1.2%) treated subjects vs. none in placebo. Rates of GI infections (>1%overall) and serious infections (1.4% drug treated vs. 1.8% placebo) were similar between treatment groups. Similarly, there was no increase in rates of systemic infections (eg pneumonia, pyelonephritis) in drug treated subjects. To date, no systemic OIs have been reported during any clinical trial (including in an ongoing open-label study in which 53 subjects have received ' 7 doses of vedolizumab [>1 year exposure]). One patient with UC who received one dose of drug developed a primary cytomegalovirus infection 21 days later that resolved without antiviral therapy. Vedolizumab was not associated with lymphocytosis or increases in other WBC subsets. Rates of LFT abnormalities were similar to placebo. In these multiple dose studies, 2 (<1%) subjects who received drug developed an infusion related hypersensitivity reaction. There were no cases of PML or JC viremia in vedolizumab subjects. CONCLUSIONS: Vedolizumab has been well-tolerated to date with no increase in systemic infections and a possible trend in increased upper respiratory and mucosal infections. These data and the absence of lymphocytosis are consistent with the target specificity of vedolizumab and the distribution of MAdCAM-1 in mucosal tissue. The selectivity of vedolizumab for alpha4beta7 and the GI-specific function of alpha4beta7, provide regional immunomodulation of the GI tract with less potential for systemic immunosuppression. This promising profile will be further defined in ongoing Phase 3 trials in UC and CD.