Treatment of ulcerative colitis and Crohn’s disease: safety of Vedolizumab

Crohn’s disease and ulcerative colitis are chronic, relapsing inflammatory disorders of the gastrointestinal ( GI ) tract. In both Crohn’s disease and ulcerative colitis, leukocytic infiltration of the mucosa is associated with epithelial damage. Recently, monoclonal antibodies directed against cell adhesion molecules ( CAMs ) involved in leukocyte extravasation have been developed.
Natalizumab, the first drug brought to market targeting CAMs, is clinically effective but is associated with serious adverse effects including the uncommon, but often fatal, neurological disease progressive multifocal leukoencephalopathy.
Vedolizumab targets a subset of the CAMs blocked by Natalizumab and is currently in Phase III trials to study its efficacy and safety in patients with inflammatory bowel disease.

Vedolizumab ( Entyvio ) is a humanized monoclonal antibody that is designed to specifically antagonize the alpha4beta7 integrin, inhibiting the binding of alpha4beta7 to intestinal mucosal addressin cell adhesion molecule 1 ( MAdCAM-1 ) and fibronectin, but not vascular cell adhesion molecule 1 ( VCAM 1 ).
MAdCAM-1 is preferentially expressed on blood vessels and lymph nodes of the gastrointestinal tract.
The alpha4beta7 integrin is expressed on a subset of circulating white blood cells. These cells have been shown to play a role in mediating the inflammatory process in ulcerative colitis and Crohn’s disease. By inhibiting alpha4beta7, Vedolizumab may limit the ability of certain lymphocytes to infiltrate gut tissues.

In total, 579 patients or volunteers have participated in either Phase I or Phase II trials with 415 patients having received at least one dose of Vedolizumab. There is limited information regarding an additional 374 patients participating in GEMINI I, a phase III trial. There was no significant difference in adverse events between patients receiving Vedolizumab and those receiving placebo.
The most common adverse events reported have been headache, nausea, exacerbation of ulcerative colitis, abdominal pain, fatigue and nasopharyngitis. Importantly, no cases of PML ( progressive multifocal leukoencephalopathy ) have been reported.
A retrospective study examining 800 subjects from nine clinical trials, including ongoing Phase III trials, reported no association between exposure to Vedolizumab and JC viremia in patients receiving up to 19 doses for up to 2.5 years. Furthermore, no increased risk of serious infection, systemic opportunistic infection or malignancy was reported in these short-term studies. However, one case of primary cytomegalovirus infection occurred in a patient who received two doses of Vedolizumab. The patient improved without the need for antiviral therapy. There have been no on-study deaths reported.

In a dose-ranging study of Vedolizumab, two out of 37 patients developed pyrexia. No patients developed other signs of an infusion reaction. Two patients experienced serious adverse events that were determined later to be unrelated to Vedolizumab: osteoporosis and gastroduodenitis; one patient with a history of osteoporosis who was randomized to the 10-mg/kg group developed compression fractures of multiple thoracic vertebrae; one patient with a history of chronic gastroduodenitis who was randomized to the 2-mg/kg group developed gastroduodenitis 169 days after her last dose of Vedolizumab and esophagogastroduodenoscopy revealed esophagitis and an exacerbation of her gastroduodenitis.
There were no cases of opportunistic infections, including PML.
Additionally, there were no changes in white blood cell subsets or counts between individuals treated with Vedolizumab and those receiving placebo. In this Phase II trial, human antihuman antibodies ( HAHAs ) were detected in four patients studied ( 11% ), three from the 2 mg/kg cohort and one from the 6 mg/kg cohort. One HAHA-positive patient ( maximum titer 1:15, 625 ) from the 2-mg/kg cohort was found to have accelerated clearance of Vedolizumab. The remaining three HAHA-positive patients did not clear the drug at an accelerated rate, although their titers were less than or equal to 1:15. All patients completed the study. There were no infusion reactions observed. ( Xagena )

McLean LP et al, Immunotherapy 2012; 4: 883–898



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