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estimated at 50% by 30 years and 68% by 70 years [ 30 ]. The main risk factors for
PML in natalizumab-treated patients in addition to JCV virus seropositivity, how-
ever, are the duration of natalizumab treatment (more than 2 years) and prior use of
immunosuppressive therapy [ 31 ]. Further clinical experience with natalizumab has
been limited by the PML risk, with approval in the USA, under strict vigilance of
the TOUCH programme. It is also available in Russia and Switzerland but not in the
European Union [ 1 , 32 – 35 ].
AJM300 (Anti-α 4 Integrin)
AJM300 is an orally active and highly specific α4 integrin inhibitor with demon-
strated efficacy in a murine model of colitis [ 36 ]. Takazoe and colleagues ran-
domised 71 CD patients to receive placebo, oral AJM300 at 40 mg, 120 mg and
240 mg, three times daily for 8 weeks [ 38 ]. CDAI reduction at week 4, in AJM300
groups, was higher than in the placebo group, but differences were not statistically
significant. The drug was well tolerated at doses of 120 mg and 240 mg three times
daily [ 38 ]. Yoshimura and colleagues conducted a randomised double-blind placebo-
controlled phase IIA trial in patients with moderately active UC [ 37 ]. A clinical
response (primary endpoint) was achieved in 62.5% in the AJM300 group vs. 25.5%
given placebo. Clinical remission rates (Mayo Clinic score ≤ 2 and no subscore >1)
were 23.5% and 3.9% in the AJM300 group and placebo groups, respectively
(OR = 7.81; 95% CI: 1.64–37.24; P = 0.0099), and rates of mucosal healing (endo-
scopic subscores of 0 or 1) were 58.8% and 29.4% (OR = 4.65; 95% CI: 1.81–11.90;
P = 0.0014). No serious adverse events including progressive multifocal leucoen-
cephalopathy were observed [ 37 ].
Vedolizumab
Vedolizumab is a humanised monoclonal IgG1 antibody which selectively binds to
the α 4 β7 integrin and has been approved for the treatment of patients with moderate
to severe UC and CD, by both FDA and the European Medicines Agency [ 38 , 39 ].
Feagan and colleagues reported the first multicentre, double-blind, placebo-
controlled trials of MLN 0002 in two separate studies of similar design [ 40 , 41 ].
Patients received intravenous infusion of MLN 0002 at 0.5 mg/kg, 2.0 mg/kg or
placebo on days 1 and 29. In the UC study with 181 patients, clinical remission at
6 weeks was achieved in 33%, 32% and 14% for the group receiving MLN 0002 at
0.5 mg/kg, 2.0 mg/kg and respectively (P = 0.03) [ 40 ]. Corresponding clinical
response rates were 66%, 53 and 33%, respectively (P = 0.007). Endoscopic remis-
sion was achieved in 28% of patients receiving 0.5 mg/kg MLN 0002 and 12% of
patients receiving 2.0 mg/kg, compared with 8% of those receiving placebo
(p = 0.007) [ 40 ].
J.K. Limdi and F.A. Farraye