On March 20, 2014, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended granting a marketing authorization for the cell adhesion molecule (CAM) inhibitor vedolizumab (Takeda's Entyvio) for the treatment of adult patients with moderate to severe active ulcerative colitis (UC) and Crohn's disease (CD). In March 2013, Takeda filed an MAA with EMA based on the GEMINI Phase III pivotal trials. We expect the European Commission to adopt the CHMP recommendation and grant vedolizumab full approval.

In UC, vedolizumab's Phase III trial (GEMINI I) showed promising efficacy in both induction and maintenance of remission. Currently, TNF-inhibitors are the only biologic therapies approved by EMA for moderate to severe UC (Janssen/Merck/Mitsubishi Tanabe's Remicade and Simponi and AbbVie/Eisai's Humira). Although European gastroenterologists note good clinical results achieved in UC patients by the TNF- inhibitors (particularly with Remicade), they also note that a large proportion of patients lose response within a year of treatment, and a new mechanism of action different from that of the TNF-inhibitors is a welcome option. We do not believe vedolizumab to replace Remicade as the leading biologic treatment for moderate to severe UC; instead, its use will most likely be reserved for TNF-refractory patients.

Phase III data for CD were not as positive. In the GEMINI II trial, vedolizumab did not meet its primary endpoint of induction of remission at 6 weeks, although it did show promising maintenance data at 52 weeks. In an additional Phase III induction trial (GEMINI III), vedolizumab achieved encouraging induction of remission results at 10 weeks, suggesting a slower onset of action in CD. The two already EMA approved TNF inhibitors (Remicade and Humira) show good clinical results in moderate to severe CD patients. However, very limited options are available for TNF--refractory patients. The CAM inhibitor natalizumab (Biogen Idec's Tysabri, which received EMA approval for multiple sclerosis, but failed to gain marketing authorization for CD) is sometimes used off-label in Europe for patients who fail anti-TNF- agents. However, due to the potential risk of progressive multifocal leukoencephalopathy (PML), natalizumab is reserved as a last resort to patients who are JC virus negative. With no reported cases of PML in the vedolizumab-treated patients to date, European gastroenterologists assume a low potential risk of PML owing to vedolizumab's gut-specific mechanism of action. We expect vedolizumab to be reserved as a later-line biologic in moderate to severe CD TNF- refractory patients.

Vedolizumab's FDA PDUFA date for UC and CD is scheduled for May 20 and June 18, 2014, respectively. On December 9, 2013, the FDA Joint Meeting of the Gastrointestinal Drugs Advisory Committee (GIDAC) & Drug Safety and Risk Management Advisory Committee (DSaRM) voted in favor for approval for both UC and CD, stating that the benefits outweigh the risks. We expect FDA approval for both indications.

Adi Reske is an analyst with the Immunology team at Decision Resources Group.

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