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FDA Advisors See PML Risk With Colitis Drug Vedolizumab

Risk may be similar to that of natalizumab (December 5)

Two FDA advisory panels — the Gastrointestinal Drugs Advisory Committee (GIDAC) and the Drug Safety and Risk Management Advisory Committee (DSaRMAC) — have expressed concern that treatment with vedolizumab (proposed trade name, Entyvio), an experimental drug intended for the treatment of ulcerative colitis and Crohn’s disease, may cause progressive multifocal leukoenceophalopathy (PML), an opportunistic brain infection caused by the human polyomavirus John Cunningham virus (JCV).

The opinion was announced in advance of a formal committee meeting scheduled for December 9.

Vedolizumab is a monoclonal antibody designed to control inflammation by blocking a protein receptor called alpha4beta7 integrin.

Although no cases of PML were observed during the vedolizumab clinical development program, the FDA advisors expressed concern about the risk of PML with vedolizumab because its purported mechanism of action (the disruption of integrin function) is similar to that of natalizumab (Tysabri, Biogen Idec), a product that has been associated with PML.

The advisors noted that with natalizumab, longer treatment duration (particularly more than 24 months), prior treatment with an immunosuppressant, and the presence of anti-JCV antibodies were associated with an increased risk of PML. However, for vedolizumab, the potential risk factors for PML are not known, as no cases have been reported in treated patients.

The drug’s developer (Takeda) has asserted that vedolizumab does not have the same risk of PML as natalizumab because of mechanistic differences between the two products (mainly in their receptor-binding targets), and that in vitro activity data, animal models, and human pharmacodynamic data suggest a lower risk of PML than for natalizumab. The FDA reviewers questioned whether these data provide sufficient evidence of a lower PML risk with vedolizumab compared with natalizumab.

In their opinion, if vedolizumab is approved, a risk-management strategy (beyond labeling) may be required to address the potential risk of PML.

Source: FDA; December 5, 2013.

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