304
Leukocyte Trafficking Antagonists
Vedolizumab (Anti-α 4 β7 Integrin, Monoclonal Ab, IV Route,
UC/CD)
Vedolizumab, a monoclonal antibody that targets the α 4 β7 integrin, was approved
by the FDA in May of 2014 for use in UC and Crohn’s disease. α 4 β7 integrin, a
cell-surface glycoprotein variably expressed in circulating B and T lymphocytes,
interacts with mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1),
its counter-receptor found preferentially in the intestinal vasculature [ 2 ]. By block-
ing the α 4 β7 integrin, vedolizumab mediates leukocyte trafficking to the gut [ 3 ].
The integrins found to be important for the gastrointestinal tract include α 2 β2, α 4 β1,
and α 4 β7 [ 4 ]. They can, of course, be found in other organs as well besides the gut.
Vedolizumab is not the first anti-integrin approved for the treatment of
IBD. Natalizumab, a monoclonal antibody that targets both the α 4 β1 and α 4 β7 inte-
grins found in the gut, blocks trafficking not only in the gut but also the brain. α 4 β 1
integrins are also involved in leukocyte trafficking in the brain [ 2 ]. Natalizumab was
approved by the FDA in January 2008 for use in moderate to severe Crohn’s disease.
Although efficacy data was compelling [ 5 ], reports of a 2.1 per 1000 risk of progres-
sive multifocal leukoencephalopathy (PML) [ 6 ], a serious brain infection, relegated
its use to second-line salvage therapy. The typical patient is low risk for PML (nega-
tive JC virus serology) and has failed TNF therapy [ 7 ].
In contrast to natalizumab, vedolizumab more selectively targets the α 4 β7 integ-
rin receptor, found primarily in gut-specific lymphocytes. It does not target the α 4 β 1
integrin, found in the gut and the brain [ 8 ]. Based on this gut-selective mechanism,
the lack of reported cases of PML to date [ 9 ], and clinical trial data [ 2 , 8 ], it was
FDA approved as first-line therapy for the treatment of moderate to severe Crohn’s
disease and ulcerative colitis. Specific monitoring for PML or JC virus serology is
not required.
Phase III randomized controlled trials provide the evidence base demonstrating
the efficacy of vedolizumab. GEMINI I enrolled patients with moderate to severe
Table 17.1 Novel biologic agents by mechanism of action and current status
Crohn’s disease Mechanism Ulcerative colitis
Vedolizumab (approved) Anti-integrin Vedolizumab (approved)
Etrolizumab (phase III) Etrolizumab (phase III)
PF-00547659 (phase II) PF-00547659 (phase II)
Ozanimod (phase II) Sphingosine-1-phosphate
inhibitorOzanimod (phase III)Ustekinumab (approved) Anti-IL12 and/or IL23 Ustekinumab (phase III)
Risankizumab (phase II)
Filgotinib (phase III) Janus kinase inhibition Tofacitinib (awaiting approval)
Filgotinib (phase III)
Mongerson (phase III) Anti-SMAD7 Mongerson (phase II)F. Velayos