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P231. No association between vedolizumab exposure and serum JC virus levels

A. Parikh1, J. Paolino1, E.R. Fedyk1, D. Clifford2, J. Berger3, S. Sankoh1, I. Fox1, C. Milch1

1Millennium Pharmaceuticals, Cambridge, MA, United States; 2Dept of Neurology, Washington University in St Louis, St Louis, MO, United States; 3Dept of Neurology, University of Kentucky, Lexington, KY, United States

Aim: Vedolizumab (previous versions MLN0002, MLN02, LDP-02) is a gut-selective biologic in phase 3 development for treatment of ulcerative colitis and Crohn's disease. Vedolizumab binds to the α4β7 integrin, antagonizes the interaction with MAdCAM-1 and thereby prevents migration of memory T lymphocytes into the gastrointestinal tract. Vedolizumab binds to the α4β7 but not the α4β1 integrin. Natalizumab, which binds both the α4β7 and α4β1 integrin, has been associated with progressive multifocal leukoencephalopathy (PML), a rare but frequently fatal CNS infection caused by JC virus. Vedolizumab's gut selectivity raises the prospect of achieving a beneficial therapeutic effect in IBD without reactivating JCV or affecting brain immunosurveillance. As of 31 October 2010, >2100 subjects have received ≥1 doses of vedolizumab for ≤3 years, with no reported cases of PML. Studies of the relationship between JCV and natalizumab exposure have produced conflicting results, with at least two studies suggesting exposure may increase detectable viremia over time. We therefore sought to determine whether exposure to vedolizumab would also increase detectable JC viremia in serum, and if exposure duration relates to viremia.

Methods: JC viremia was longitudinally assessed using frozen serum samples collected at approximately 2-month intervals from >2000 subjects enrolled in 9 vedolizumab clinical trials, including completed phase 1 and 2 studies and ongoing blinded and open-label phase 3 studies. A positive result was defined as any sample with ≥30 copies/mL (assay threshold). Persistent viremia was defined as detectable viremia on two successive samplings within a 6-month period performed ≥1 month apart. The relationship between duration of vedolizumab exposure and viremia was analyzed, assuming patients in blinded placebo-controlled trials received vedolizumab at all infusions.

Results: JC virus testing revealed no association between vedolizumab exposure and viremia. Incidence of JC viremia on a per patient basis was 0.5%, with 9 of ∼2000 patients testing positive. Five patients had detectable viremia at baseline (before vedolizumab dosing). One of these had two subsequent, consecutive positive results (meeting the definition of persistent viremia); the third subsequent sample was negative. In three other patients with detectable viremia at baseline, viremia cleared spontaneously, possibly in the presence of therapeutic vedolizumab serum concentrations. The fifth patient was lost to follow-up. Four patients developed detectable viremia post-baseline. Viremia subsequently cleared spontaneously in all four. JC viremia occurrence did not increase as a function of exposure duration.

Conclusion: We previously reported that JC viremia in subjects receiving vedolizumab likely represents a stochastic event not influenced by vedolizumab exposure. Accumulating experience from phase 3 trials strengthens this conclusion and suggests no relationship to exposure duration. The data also demonstrate evidence of spontaneous clearance of viremia (including persistent viremia) in the presence of vedolizumab.